Reactive yellow dyes useful for ocular devices

ABSTRACT

Novel azo-based reactive yellow dyes and a process for manufacturing and using ocular devices having blue light absorption properties. Intraocular lenses so produced block blue light from reaching the retina of an eye implanted with the IOL. By blocking blue light from reaching the retina, the IOL thereby prevents potential damage to the retina.

CROSS-REFERENCE OF RELATED APPLICATION

This application is a divisional of U.S. application Ser. No. 10/657,495filed Sep. 8, 2003, now U.S. Pat. No 7,098,283.

FIELD OF THE INVENTION

The present invention relates to a process for making ocular deviceswith blue light absorption properties. More particularly, the presentinvention relates to novel yellow dyes having vinyl polymerizable groupscapable of copolymerization with monomers and/or oligomers to producecopolymers useful in the manufacture of intraocular lenses or otheroptical devices capable of blocking blue light.

BACKGROUND OF THE INVENTION

Since the 1940's optical devices in the form of intraocular lens (IOL)implants have been utilized as replacements for diseased or damagednatural ocular lenses. In most cases, an intraocular lens is implantedwithin an eye at the time of surgically removing the diseased or damagednatural lens, such as for example, in the case of cataracts. Fordecades, the preferred material for fabricating such intraocular lensimplants was poly(methyl methacrylate), which is a rigid, glassypolymer.

Softer, more flexible IOL implants have gained in popularity in morerecent years due to their ability to be compressed, folded, rolled orotherwise deformed. Such softer IOL implants may be deformed prior toinsertion thereof through an incision in the cornea of an eye. Followinginsertion of the IOL in an eye, the IOL returns to its originalpre-deformed shape due to the memory characteristics of the softmaterial. Softer, more flexible IOL implants as just described may beimplanted into an eye through an incision that is much smaller, i.e.,less than 4.0 mm, than that necessary for more rigid IOLs, i.e., 5.5 to7.0 mm. A larger incision is necessary for more rigid IOL implantsbecause the lens must be inserted through an incision in the corneaslightly larger than the diameter of the inflexible IOL optic portion.Accordingly, more rigid IOL implants have become less popular in themarket since larger incisions have been found to be associated with anincreased incidence of postoperative complications, such as inducedastigmatism.

With recent advances in small-incision cataract surgery, increasedemphasis has been placed on developing soft, foldable materials suitablefor use in artificial IOL implants. Mazzocco, U.S. Pat. No. 4,573,998,discloses a deformable intraocular lens that can be rolled, folded orstretched to fit through a relatively small incision. The deformablelens is inserted while it is held in its distorted configuration, thenreleased inside the chamber of the eye, whereupon the elastic propertyof the lens causes it to resume its molded shape. As suitable materialsfor the deformable lens, Mazzocco discloses polyurethane elastomers,silicone elastomers, hydrogel polymer compounds, organic or syntheticgel compounds and combinations thereof.

In recent years, blue light (400-500 nm) has been recognized as beingpotentially hazardous to the retina. Accordingly, yellow dyes to blockblue light have been used in foldable intraocular lenses, in conjunctionwith ultraviolet light absorbers, to avoid potential damaging effects.Freeman et al., U.S. Pat. No. 6,353,069, disclose high refractive indexcopolymers comprising two or more acrylate and/or methacrylate monomerswith aromatic groups. Ophthalmic devices made of the copolymers may alsoinclude colored dyes, such as the yellow dyes disclosed in U.S. Pat. No.5,470,932. Such materials exhibit sufficient strength to allow devicesmade of them, such as intraocular lenses, to be folded or manipulatedwithout fracturing.

Because of the ophthalmic risks associated with blue light exposure, newmaterials and methods of manufacturing ophthalmic devices are needed toaid in minimizing or eliminating such risks.

SUMMARY OF THE INVENTION

Soft, foldable, high refractive index, ocular devices, such as forexample intraocular lenses (IOLs), capable of absorbing blue light areprepared in accordance with the present invention through the use of oneor more novel reactive yellow dyes having blue light absorbingproperties. Blue light absorbing ocular devices, such as IOLs, areproduced in accordance with the present invention through thecopolymerization of one or more novel yellow dyes having vinylpolymerizable groups, with one or more acrylic-type monomers and/or oneor more siloxane oligomers. Ocular devices so produced protect an eye'sretina from potentially damaging blue light and thereby possibly provideprotection from macular degeneration.

Blue light blocking ocular devices of the present invention are producedby copolymerizing one or more novel yellow dyes having vinylpolymerizable groups with one or more acrylic-type monomers and allowingthe same to undergo free radical copolymerization. Alternatively, oculardevices of the present invention may be produced by copolymerizing oneor more novel yellow dyes having vinyl polymerizable groups with one ormore siloxane oligomers having hydrosilane groups through ahydrosilation reaction. Such production processes yield ocular deviceswith blue light absorbing properties. By absorbing blue light, theocular devices serve to block blue light from reaching and potentiallydamaging the retina of an eye implanted with the device. Ocular devices,such as IOLs so produced are transparent, relatively high in elongationand relatively high in refractive index.

Accordingly, it is an object of the present invention to provide aprocess for the production of ocular devices capable of absorbing bluelight.

Another object of the present invention is to provide a process for theproduction of ocular devices having relatively high refractive indicesand good clarity.

Another object of the present invention is to provide a process for theproduction of ocular devices that are flexible.

Still another object of the present invention is to providebiocompatible ocular devices capable of absorbing blue light.

These and other objectives and advantages of the present invention, someof which are specifically described and others that are not, will becomeapparent from the detailed description and claims that follow.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a series of novel azo-based reactiveyellow dyes useful in the production of high refractive index oculardevices such as for example but not limited to IOLs. Ocular devicesproduced using the azo-based reactive yellow dyes of the presentinvention have blue light absorption properties that reduce or preventblue light from reaching the retina of an eye implanted with the oculardevice. Azo-based reactive yellow dyes of the present invention havevinyl polymerizable groups such as for example but not limited toitaconic, fumatate, maleic, vinylacetyl, crotonic, or derivativesthereof, styrene, norbornenyl, vinyl, allyl, or like alkenyl groups. Theazo-based reactive yellow dyes' vinyl polymerizable groups allow thesame to copolymerize with acrylic-type monomers through free radicalcopolymerization, or with siloxane oligomers having hydrosilane groupsthrough a hydrosilation reaction.

Azo-based yellow dyes of the present invention have the generalizedstructure illustrated in Formula 1 below.Ar₁—N═N—Ar₁—(R₁)—NR₂—(R₃—CR₄═CHR₅)_(m)  FORMULA 1Here, the Ar₁ groups represent the same or different, substituted orunsubstituted C₆₋₃₆ aromatic groups such as for example but not limitedto phenyl or naphthyl, which are responsible for providing blue lightabsorption properties to the yellow dye; R₁ is nothing or a straight orbranched C₁₋₁₀ alkylene spacer consisting of one or more of the atoms C,H, N, O, S, P, Si, Cl or Br in any combination; R₂ is hydrogen or aC₁₋₁₀ alkyl such as for example but not limited to methyl, butyl orhexyl when m is 1, or is nothing when m is 2; R₃ is nothing, a straightor branched C₁₋₁₀ alkylene spacer consisting of one or more of the atomsC, H, N, O, S, P, Si, Cl or Br in any combination, or when R₄ isCH₂COOR₂ or R₅ is COOR₂, a carbonyl group; R₄ is hydrogen, a C₁₋₁₀ alkylsuch as for example but not limited to ethyl, propyl or pentyl, orCH₂COOR₂; R₅ is hydrogen, a C₁₋₁₀ alkyl such as for example but notlimited to methyl, propyl or butyl, or COOR₂; and m is 1 or 2.

Depending on the structure of the novel azo-based yellow dye to besynthesized, the yellow dye can be prepared by two different syntheticschemes. Both synthetic schemes involve diazotization of an aromaticamine, followed by coupling with different groups of interest dependingon the desired structure of the yellow dye being synthesized. As forexample, one synthetic scheme can be initiated by the reaction ofN-phenyl diethanolamine with a diazonium salt of aniline, followed by areaction with a vinyl-containing acid chloride or isocyanate to producea reactive yellow dye. The same is further illustrated in ReactionScheme 1 below.

Another reaction scheme involves reaction of an aromatic alkylamine witha vinyl-containing acid chloride, anhydride or isocyanate to give anethylenically unsaturated polymerizable amide or carbamate. The same isthen allowed to couple with the diazonium salt of an aromatic amine toproduce a yellow dye as illustrated in Reaction Scheme 2 below.

Preferred reactive yellow dyes of the present invention useful in themanufacture of ocular devices with blue light absorbing propertiesinclude for example but are not limited toN-2-[3′-(2″-methylphenylazo)-4′-hydroxyphenyl]ethyl vinylacetamideillustrated below in Formula 2,N-2-[3′-(2″-methylphenylazo)-4′-hydroxyphenyl]ethyl maleimideillustrated below in Formula 3,N,N-bis-(2-vinylacetoxyethyl)-(4′-phenylazo)aniline illustrated below inFormula 4 and N,N-bis-(2-allylcarbamatoethyl)-(4′-phenylazo)anilineillustrated below in Formula 5.

Reactive yellow dyes of the present invention synthesized as describedabove can be used in the manufacture of blue light blocking oculardevices by copolymerizing one or more of the subject reactive yellowdyes having polymerizable groups with one or more acrylic-type monomersand allowing the same to undergo free radical copolymerization.Alternatively, ocular devices of the present invention may be producedby copolymerizing one or more of the subject reactive yellow dyes havingpolymerizable groups with one or more siloxane oligomers havinghydrosilane groups through a hydrosilation reaction using aplatinum-silicone complex as a catalyst. Such production processes yieldocular devices with blue light absorbing properties. Reactive yellowdyes of the present invention may also be used to impart blue lightabsorption properties to a semi-finished silicone ocular device such asfor example but not limited to an IOL. A “semi-finished” silicone IOLfor purposes of the present invention, is a silicone IOL having freehydrosilyl groups.

Suitable acrylic-type monomers for copolymerization with one or morereactive yellow dyes of the present invention include for example butare not limited to 2-ethylphenoxy methacrylate, 2-ethylphenoxy acrylate,2-ethylthiophenyl methacrylate, 2-ethylthiophenyl acrylate,2-ethylaminophenyl methacrylate, 2-ethylaminophenyl acrylate, phenylmethacrylate, benzyl methacrylate, 2-phenylethyl methacrylate,3-phenylpropyl methacrylate, 2-(4-propylphenyl)ethyl methacrylate,2-(4-(1-methylethyl)phenyl)ethyl methacrylate, 2-(4-methoxyphenyl)ethylmethacrylate, 2-(4-cyclohexylphenyl)ethyl methacrylate,2-(2-chlorophenyl)ethyl methacrylate, 2-(3-chlorophenyl)ethylmethacrylate, 2-(4-chlorophenyl)ethyl methacrylate,2-(4-bromophenyl)ethyl methacrylate, 2-(3-phenylphenyl)ethylmethacrylate, 2-(4-phenylphenyl)ethyl methacrylate,2-(4-benzylphenyl)ethyl methacrylate, methacrylate, 4-methylphenylmethacrylate, 4-methylbenzyl methacrylate, 2,2-methylphenylethylmethacrylate, 2,3-methylphenylethyl methacrylate and methacrylate-cappedprepolymers with multiple blocks ofpolydimethyl-co-diphenyl-co-methylphenyl siloxanes linked with urethanelinkages.

Suitable siloxane oligomers for copolymerization with one or morereactive yellow dyes of the present invention include for example butare not limited to vinyl-capped prepolymers of high refractive indexpolysiloxanes such as α,ω-divinyl polydimethyl-co-diphenyl siloxane,silicone resin with multiple vinyl groups and trimethylsiloxy-terminatedpolydimethyl-co-methylhydrosiloxane.

The process of the present invention for preparing flexible, highrefractive index ocular devices with blue light absorption properties isdescribed in still greater detail in the Examples provided below.

EXAMPLE 1 Synthesis of N,N-bis-(2-hydroxyethyl)-(4-phenylazo)aniline(Solvent Yellow 58)

The synthesis of N,N-bis-(2-hydroxyethyl)-(4-phenylazo)aniline isaccomplished by coupling the diazonium salt of aniline with N-phenyldiethanolamine. A detailed procedure is also described in D. L.Jinkerson, U.S. Pat. No. 5,470,932, incorporated herein in its entiretyby reference.

EXAMPLE 2 Synthesis ofN,N-bis-(2-allylcarbamatoethyl)-(4′-phenylazo)aniline

A 1000-mL 3-neck, round bottom flask connected with a reflux condenserand a drying tube, is charged with 250 mL of methylene chloride, 5.7grams (0.02 mole) of N,N-bis-(2-hydroxyethyl)-(4-phenylazo)aniline, 3.28g of allyl isocyanate (0.04 mole) (Aldrich Chemical, Inc., Milwaukee,Wis.) and 0.014 g of dibutyltin dilaurate (Aldrich Chemical). Themixture is heated and refluxed overnight under vigorous stirring. Themixture is then checked with infrared spectroscopy and no residualisocyanate peak is found indicating the reaction is complete. Themixture is concentrated using a rotavapor. High performance liquidchromatography (HPLC) analysis indicates only one major product. Theproduct is then passed through silica gel chromatography to give finalpurified product with a yield of at least 80 percent. The product isidentified by nuclear magnetic resonance (NMR) and Mass Spectroscopy.

EXAMPLE 3 Synthesis ofN,N-bis-(2-vinylacetoxyethyl)-(4′-phenylazo)aniline

A 1000-mL 3-neck, round bottom flask connected with a reflux condenserand a drying tube, is charged with 250 mL of methylene chloride, 5.7grams (0.02 mole) of N,N-bis-(2-hydroxyethyl)-(4-phenylazo)anilineaniline and 4.04 grams of triethylamine (0.04 mole). The contents arechilled with an ice bath. Through a dropping funnel, 4.18 g (0.04 mole)of vinylacetyl chloride is added into the flask over a period of 30minutes. The ice bath is then removed and the contents are continuouslystirred overnight. The mixture is then filtered and then condensed usinga rotavapor. HPLC analysis indicates only one major product. The productis then passed through silica gel chromatography to give a finalpurified product with a yield of at least 80 percent. The product isidentified by NMR and Mass Spectroscopy.

EXAMPLE 4 Synthesis ofN-2-[3′-(2″-methylphenylazo)-4′-hydroxyphenyl]ethyl vinylacetamide

N-2-[3′-(2″-methylphenylazo)-4′-hydroxyphenyl]ethyl vinylacetamide canbe made in two steps. The first step is the formation of4-vinylacetamidoethyl phenol. The second step is the coupling of azoniumsalt of toluidine with the phenol to give the product.

Step 1. Synthesis of 4-vinylacetamidoethyl phenol.

A 1000 mL 3-neck, round bottom flask connected with a reflux condenserand a drying tube, is charged with 250 mL of methylene chloride, 5.48grams (0.04 mole) 4-aminoethylphenol and 4.04 grams (0.04 mole)triethylamine. The contents are chilled with an ice bath. Through adropping funnel, 4.18 grams (0.04 mole) of vinylacetyl chloride is addedinto the flask over a period of 30 minutes. The ice bath is then removedand the contents are continuously stirred overnight. The mixture is thenfiltered and then condensed using a rotavapor. HPLC analysis indicatesonly one major product. The product is then passed through silica gelchromatography to give a final purified product with a yield of at least80 percent. The product is identified by NMR and Mass Spectroscopy.

Step 2. Coupling of Product from Step 1 with Toluidine Diazonium Salt.

The procedure is the same as that described in U.S. Pat. No. 5,470,932,Example 1, second half except the acrylamidoethyl phenol is replacedwith 4-vinylacetamidoethyl phenol. The product is identified by NMR andMass Spectroscopy.

EXAMPLE 5 Preparation of Yellow Dye Solution for Coating of an IOL

Solutions containing 1, 2, 5 and 10 weight percent of the yellow dye ofExample 4 in methylene chloride is prepared. To these solutions,platinum-cyclovinylmethylsiloxne complex (Gelest, Inc., Tullytown, Pa.)at 1% of the weight of the yellow dye is also added.

EXAMPLE 6 Coating of Silicone Intraocular Lenses

Ten (10) freshly thermally cured SoFlex™ Model LI61U (Bausch & Lomb,Incorporated, Rochester, N.Y.) lenses are submerged into each coatingsolution as described in Example 3 for 30, 60 and 120 minutes. Takes outlenses and air dry them. Then place these lenses in an oven at 80 to 90°C. for an hour. These lenses are then subjected to standard processingto get the final finished product.

Model LI61U lenses are silicone IOLs derived from components consistingof a vinyl terminated polydimethyl-co-diphenyl siloxane, silicon-basedreinforcing resins with vinyl groups, and an oligomer with multihydrosilane units. Model LI61U silicone lenses have excess freehydrosilane groups after curing.

EXAMPLE 7 Selection of Yellow Dye Concentration and Coating Conditions

Run ultraviolet (UV) and visible absorption spectroscopy of coatedlenses before and after processing. Select the yellow dye concentrationand residence time of lens in dye solution based on the visible lightabsorption of the process lenses between 400-500 nm. Conditions, whichgive less than 50% transmittance and maintenance of lens power/cosmeticsare chosen for further coating studies, followed by optimization ofconditions.

Soft, foldable, relatively high refractive index of approximately 1.42or greater, relatively high elongation of approximately 100 percent orgreater, IOLs with blue light absorption properties are synthesizedthrough the process of the present invention. Suitable catalysts for usein the process of the present invention, for a hydrosilation reaction,include but are not limited to platinum(3-3.5%)-divinyltetramethyldisiloxane complex and platinum(3-3.5%)-cyclovinylmethylsiloxane complex.

The IOLs produced as described herein have the flexibility required toallow the same to be folded or deformed for insertion into an eyethrough the smallest possible surgical incision, i.e., 3.5 mm orsmaller. It is unexpected that the subject IOLs described herein couldpossess the ideal physical properties disclosed herein. The idealphysical properties of the subject IOLs are unexpected because changesin mechanical properties such as modulus, percent elongation and tearstrength can occur upon addition of the reactive dye functional groups.

IOLs manufactured in accordance with the present invention can be of anydesign capable of being rolled or folded for implantation through arelatively small surgical incision, i.e., 3.5 mm or less. Such IOLs maybe manufactured to have an optic portion and haptic portions made of thesame or differing materials. Once the material(s) are selected, the samemay be cast in molds of the desired shape, cured and removed from themolds. After such molding, the IOLs are treated in accordance with theprocess of the present invention and then cleaned, polished, packagedand sterilized by customary methods known to those skilled in the art.

In addition to IOLs, the process of the present invention is alsosuitable for use in the production of other medical or ophthalmicdevices such as contact lenses, keratoprostheses, capsular bag extensionrings, corneal inlays, corneal rings and like devices.

IOLs manufactured in accordance with the present invention are used ascustomary in the field of ophthalmology. For example, in a surgicalcataract procedure, an incision is placed in the cornea of an eye.Through the corneal incision the cataractous natural lens of the eye isremoved (aphakic application) and an IOL is inserted into the anteriorchamber, posterior chamber or lens capsule of the eye prior to closingthe incision. However, the subject ophthalmic devices may likewise beused in accordance with other surgical procedures known to those skilledin the field of ophthalmology.

While there is shown and described herein a process for producing oculardevices with blue light absorption properties, it will be manifest tothose skilled in the art that various modifications may be made withoutdeparting from the spirit and scope of the underlying inventive conceptand that the same is not limited to particular processes and structuresherein shown and described except insofar as indicated by the scope ofthe appended claims.

1. An ocular device comprising a copolymerization product of one or moreacrylic-type monomers, one or more siloxane oligomers or a mixture ofacrylic-type monomers and siloxane oligomers, with one or more yellowdyes selected from the group consisting of

said ocular device having blue light absorption properties.
 2. Theocular device of claim 1 wherein said ocular device is fabricated fromsemi-finished silicone.
 3. The ocular device of claim 1 wherein saidocular device is fabricated from one or more acrylic-type monomers. 4.The ocular device of claim 1 wherein said ocular device is fabricatedfrom one or more siloxane oligomers.
 5. An intraocular lens comprising acopolymerization product of one or more acrylic-type monomers, one ormore siloxane oligomers or a mixture of acrylic-type monomers andsiloxane oligomers, with one or more yellow dyes selected from the groupconsisting of

said intraocular lens having blue light absorption properties.
 6. Theintraocular lens of claim 5 wherein said lens is fabricated fromsemi-finished silicone.
 7. The intraocular lens of claim 5 wherein saidlens is fabricated from one or more acrylic-type monomers.
 8. Theintraocular lens of claim 5 wherein said lens is fabricated from one ormore siloxane oligomers.
 9. A method of using the ocular device of claim1 comprising: implanting said ocular device in an eye.
 10. A method ofusing the intraocular lens of claim 5 comprising: implanting saidintraocular lens in an eye.
 11. The ocular device of claim 1 whereinsaid ocular device is selected from the group consisting of contactlenses, keratoprostheses, capsular bag extension rings, corneal inlays,corneal rings and intraocular lenses.